Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers

Abstract

Total or near-total loss of insulin-producing β-cells is a situation found in diabetes (Type 1, T1D) 1,2. Restoration of insulin production in T1D is thus a major medical challenge. We previously observed in mice in which β-cells are completely ablated that the pancreas reconstitutes new insulin-producing cells in absence of autoimmunity 3. The process involves the contribution of islet non-β-cells; specifically, glucagon-producing α-cells begin producing insulin by a process of reprogramming (transdifferentiation) without proliferation 3. Here we studied the influence of age on β-cell reconstitution from heterologous islet cells after near-total β-cell loss. We found that senescence does not alter α-cell plasticity: α-cells can reprogram to produce insulin from puberty through adulthood, and also in aged individuals, even a long-time after β-cell loss. In contrast, prior to puberty there is no detectable α-cell conversion, although β-cell reconstitution after injury is more efficient, always leading to diabetes recovery; it occurs through a newly discovered mechanism: the spontaneous en masse reprogramming of somatostatin-producing δ-cells. The younglings display “somatostatin-to-insulin” δ-cell conversion, involving de-differentiation, proliferation and re-expression of islet developmental regulators. This juvenile adaptability relies, at least in part, upon combined action of FoxO1 and downstream effectors. Restoration of insulin producing-cells from non-β-cell origins is thus enabled throughout life via δ- or α-cell spontaneous reprogramming. A landscape with multiple intra-islet cell interconversion events is emerging, thus offering new perspectives.

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

“…The process is commonly presumed to be induced by insulin deficiency or pancreatic injury and remodeling (Chera et al, 2014;Habener and Stanojevic, 2012). Instead, our observations demonstrate that transdifferentiation between alpha and beta cells takes place within a specialized niche at the periphery of healthy islets.…”

“…This establishes that beta cells can arise from nonbeta endocrine cells in the islet via direct transdifferentiation. Indeed, near-complete ablation of pre-existing beta cells is eventually followed by the restoration of beta cell mass via transdifferentiation of non-beta endocrine cells in mice (Chera et al, 2014;Thorel et al, 2010). These studies provided important proof of principle that insulin independence can be regained by transdifferentiation, but have also led to the notion 4 that it is triggered by severe beta cell ablation and the associated pancreas remodeling (Habener and Stanojevic, 2012).…”

The Making of Pancreatic β Cells: Advances and Apprehensions

“…Exendine-4 (EX-4) [131] and Laminin 411 [132] could also be used to optimally differentiate the adipose-derived mesenchymal cells (ADMSCs) and umbilical cord MSCs, respectively, into insulin producing cells. The conversion of δ cells into β cells also is an age-dependent process [133].…”

A combination of cytokines EGF and CNTF protects the functional beta cell mass in mice with short-term hyperglycaemia

“…In adult mice, alpha cells can be an alternative source of new beta cells as shown by diphtheria toxin-induced near-total beta cell ablation [11] and by forced expression of paired box 4 (PAX4) [12], while delta-to-beta cell transdifferentiation occurs in juvenile mice following beta cell ablation [13]. Successful treatment of hyperglycaemic mice with epidermal growth factor (EGF) and gastrin [14] suggested acinar cells as a possible source of novel beta cells, but recent cell-lineage tracing rejected this hypothesis [15].…”